Salt-induced hypertension: Central regulation by ouabain-like compounds and angiotensin II.

Abstract

We hypothesized that the ventral anteroventral third ventricle region (vAV3V), which mainly comprises the organum vasculosum laminae terminalis (OVLT) and extends ∼100 mum into the median preoptic nucleus, mediates salt-induced sympathoexcitation and hypertension via AT1 receptor activation. We utilized ibotenic acid lesions of the vAV3V to determine a role of neurons in this area in pressor responses to intracerebroventricular (icv) administration of hypertonic saline (0.3M NaCl, 2 mul/min for 10 min), ouabain (0.3 and 0.6 mug) and angiotensin II (Ang II; 10 and 30 ng), and in two rat models of hypertension in which mechanisms of salt-sensitive hypertension are mimicked: chronic icv hypertonic, saline (0.8 M NaC1, 5 mul/h icv for 2 weeks) to increase CSF [Na+] and chronic subcutaneous (sc) ouabain (50 mug/d sc for 3 weeks) to mimick increases in central ouabain-like compound content. 125I-Sar1Ile8-Ang II binding to AT1 receptors was determined by in vitro receptor autoradiography to determine if changes in AT1 receptor density accompany the development of salt-induced hypertension in Dahl salt-sensitive (S) rats. In conscious vAV3V lesioned Wistar rats with systemic vasopressin receptor blockade, pressor and tachycardic responses to 0.3 M NaCl and ouabain, were significantly attenuated by 26--32% whereas responses to Ang II were unaffected. Resting mean arterial pressure (MAP) in sham-operated rats that received chronic hypertonic saline infusions or ouabain treatment was significantly higher (17--19%) than in aCSF or placebo treated controls. vAV3V lesions abolished the chronic hypertonic saline or ouabain induced increases in MAP and the enhanced depressor responses to ganglionic blockade with hexamethonium. AT1 binding in the OVLT, the suprachaismatic nucleus and the paraventricular nucleus did not differ between Dahl S and R rats on regular salt diet, and was decreased similarly on high salt diet. Within the subfornical organ AT1 receptor binding did not differ between Dahl S and R rats on regular salt diet and decreased in both strains on the high salt diet, but decreased more in hypertensive Dahl S versus the normotensive Dahl R rats (50% versus 23%). In conclusion, the vAV3V area appears to play a crucial role in mediating salt-induced hypertension, possibly via sympathetic activation, but autoradiography did not provide evidence for differential AT1 stimulation in the vAV3V.